Duct carcinoma in situ (DCIS) of the breast comprises about 20% of new breast malignancies in screened populations. Treatment consists of breast conserving surgery (BCS) in about 75% of women, usually followed by (RT), which halves the risk of new cancer events on the same side. Oral endocrine therapy (OET) further reduces the risk to the same breast by 1/3rd , and cuts the risk to the other breast by one-half. However, OET is declined by more than half of DCIS patients, given its thromboembolic and uterine risks (selective estrogen receptor modulators), and musculoskeletal effects (aromatase inhibitors). Drug delivery methods that avoid the adverse effects of these agents will represent a significant advance. Transdermal delivery is a well-recognized and effective alternative. Advantages include low systemic exposure, longer retention in the local tissue, and avoidance of first-pass hepatic metabolism. Encouraging preliminary data on local transdermal therapy (LTT) with 4-hydroxytamoxifen (4-OHT) applied to the breast skin have led us to conduct clinical trials aimed at establishing the equivalence of transdermal and oral treatment of the breast. If successful, this will be a novel and potentially transformative development for the DCIS population, and for women at high risk for breast cancer. However, there are significant knowledge gaps regarding the causes of individual variations in dermal permeation. And current studies exclude women who have undergone breast RT because this may alter dermal permeation and/or distribution through the breast. Since DCIS patients who receive RT breast derive additional protection for both breasts through the use of OET, an evaluation of drug permeation through radiated skin is important. The Aims of our study are 1) to identify the skin features that drive inter-individual variation in dermal drug permeation between individuals, and 2) to assess the feasibility of transdermal drug delivery to the radiated breast. We will do this by enrolling breast cancer survivors who have one radiated and one intact, non- radiated breast, and are willing to apply 4-OHT gel to both breasts for a period of 3-5 weeks. We will then obtain skin punch and core needle biopsies of both breasts, measure drug concentration in the breast tissue cores, and assess individual characteristics (breast size, adiposity) and skin features (thickness of skin layers, gene and protein expression) that may explain the inter-individual variation in drug concentration. In Aim 1, these features will be used to develop a predictive model that identifies the important determinants of dermal drug delivery in the unradiated breast. In Aim 2, skin features will be compared between the radiated and unradiated breast, to determine differences introduced by radiation that are important for dermal permeation. Drug concentrations will be compared between the radiated and unradiated breast. At the end, we will answer two questions regarding which little information exists currently: 1) which women are good candidates for transdermal therapy? 2) Will transdermal delivery work for the radiated breast?